In this Phase II application we propose to continue and expand the very promising line of experiments, performed during Phase I, to confirm the GI safety and therapeutic activity of a new family of phosphatidylcholine (PC) - associated nonsteroidal anti-inflammatory drugs (NSAIDs). In Phase I, we established the feasibility of modifying the formulae of PC-NSAIDs from an aqueous suspension to an oil-based formulation containing the NSAID (aspirin or ibuprofen) and equal parts of triple strength lecithin, which has benefits with regards to drug stability, cost of goods, and reduction in manufacturing steps. The data presented in the Phase I final report show that oil-based PC-ibuprofen and PC-aspirin reduced acute and chronic GI ulceration, promoted ulcer healing and had superior analgesic activity in comparison to the unmodified NSAID. In the outlined Phase II studies we propose to continue with these studies in more comprehensive chronic animal model systems, to compare PC-ibuprofen and PC-aspirin, our two lead compounds, on GI ulceration/bleeding and ulcer healing vs unmodified ibuprofen and aspirin, respectively. A similar series of experiments are also planned to compare the analgesic/anti-inflammatory activity of our test PC-NSAID formulations in acute and chronic models of hind paw inflammation. Further, we also propose a number of in vitro studies using Infrared and light scattering spectroscopy, and selective extrusion filtration techniques to demonstrate the molecular association of PC with either ibuprofen or aspirin and how this affects macromolecular structure of the lipidic particles. We also describe a number of experiments to define the molecular, cellular and physiological basis for the increased therapeutic activity of PC-NSAIDs, with a focus on membrane permeability, cyclooxygenase (COX)-inhibitory activity and bioavailability of the drugs. In the latter studies, we will investigate whether PC promotes the uptake and distribution of the NSAIDs into chylomicrons that enter the lymphatic system. Lastly, we include a series of experiments to confirm that any modification in the formulation of either oil-based PC-ibuprofen or PC-aspirin that are necessitated in response to manufacturing and stability issues, maintains the superior GI safety and therapeutic activity of this new family of NSAIDs.